The goal of this proposal is to develop and validate an intracoronary imaging device for the assessment of plaque collagen content and architecture in patients. Acute myocardial infarction (AMI), caused by the rupture of unstable plaque, is the leading cause of death worldwide. Collagen and vascular smooth muscle cells (vSMCs) together impart mechanical stability to a plaque, and a net reduction in these components is responsible for plaque rupture. Therefore, new drugs are being developed to favorably alter collagen content and stabilize unstable plaques. However, due the absence of imaging tools to accurately quantify treatment response in patients, a majority of these drugs fail in clinical trias. By facilitating the quantitative mapping of collagen and vSMC content, and plaque microstructure in coronary vessels, the technology developed in this proposal will advance current understanding of plaque vulnerability in patients, augment the drug development platform, and ultimately advance diagnosis and treatment monitoring of coronary artery disease. Our team has developed intracoronary optical frequency domain imaging (OFDI) to enable high resolution microscopy of coronary plaques. OFDI is fast becoming the new standard for intracoronary assessment worldwide. An additional source of tissue contrast is measured using polarization sensitive (PS)-OFDI that detects the polarization state of probing light to evaluate birefringence, a material property that is exhibited by collagen and vSMCs. We have previously shown that the measured birefringence is acutely related with collagen and vSMC content in atherosclerotic plaques ex vivo. However, because of high polarimetry noise in the optical system, existing PS-OFDI instrumentation is currently unreliable for intracoronary use in vivo. Therefore, our first technical goal is to overcome the limitations of the existing device and implement an advanced PS-OFDI device that will permit robust 3D birefringence microscopy in living patients. While PS-OFDI provides the advantage of sub-surface coronary microscopy, it is incapable of evaluating plaque thickness due to poor penetration of light through the necrotic core. Recent clinical studies indicate that in addition to plaque microstructure, plaque burden measured by intravascular ultrasound (IVUS) is vital to understanding plaque vulnerability and evaluating drug efficacy. Our second technical goal, therefore, is to develop a novel hybrid PS-OFDI/IVUS intracoronary console and catheter that will maintain the superior spatial resolution advantage of PS-OFDI while integrating the deep imaging capabilities of IVUS. As a result, within a single scan, this device will measure collagen architecture, plaque microstructure and plaque burden in vivo. Following technical development, we will conduct a validation study to test the accuracy of the PS- OFDI/IVUS device in atherosclerotic pigs. We will then follow the same clinical translational pathway that we used for OFDI, and conduct a clinical study to evaluate the safety, feasibility and utility of our new approach.